The development of atherosclerotic coronary artery disease is complex. Recent work indicates that plaque progression and risk of clinical events are influenced by plaque morphology and composition, local hemodynamic stresses, 3-D arterial motion, inflammation, and local vascular signaling. In Phase I of this proposal, we developed a method for 3-D and 4-D assessment of coronary artery morphology and hemodynamics by fusion of angiographic and intravascular ultrasound images. In Phase II, we will develop a method for predicting atherosclerosis progression. This predictive model, incorporating our now mature methodology with other factors, will be developed and subsequently validated in longitudinal studies of subjects with coronary atherosclerotic disease. Our main hypothesis is that serial in-vivo studies of patients with coronary artery disease can provide insights into the temporal effects of vessel morphology, plaque composition, hemodynamics, and systemic inflammatory and other vascular biomarkers on local atherosclerosis progression, thus allowing the prediction of changes in the burden, location and extent of atherosclerosis. Therefore, we propose to: Aim 1: Further improve the previously developed image analysis methodology for angiography-IVUS fusion to increase efficiency, reproducibility, and 3-D/4-D consistency of the geometric representations of coronary arteries in vivo. Aim 2: Develop a method for in vivo 3-D and 4-D assessment of complex plaque composition in registration with geometrically correct coronary anatomy and plaque morphology with the ability to incorporate functional and physiologic measures within the vasculature. Aim 3: Develop a method for predicting temporal changes in atherosclerotic plaque in vivo from multifactorial computational assessment of 3-D and 4-D coronary geometry, hemodynamics, plaque morphology and composition, with the concomitant determination of systemic atherosclerosis-related biomarkers. Aim 4: Validate the plaque progression prediction method in a serial study of 50 patients with established atherosclerosis. Our work will uncover the relative contribution of initial local plaque properties and composition, the vascular and systemic inflammatory milieu and hemodynamic conditions to intermediate-term atherosclerotic disease progression or regression. Once successfully developed, our work will uncover the interplay of these complex and disparate promoters of atherosclerosis. It will have implications on the clinical management of patients with preclinical atherosclerotic disease as well as those patients undergoing coronary revascularization and treatment of acute coronary syndromes.